Hello and welcome to this edition of joint action [Music] this podcast is dedicated to all those out there who have osteoarthritis on the show we unpack the truths and demystify the myths about the disease and its management if you have joint pain and want to know more about how to manage it from the world's best experts you've come to the Right place without further ado it is time to welcome your host david hunter hello and welcome to this week's edition of the joint action podcast where we have the opportunity to talk about prevention of osteoarthritis
following injury now in an ideal world we would prevent injuries from occurring but despite our enthusiasm to do so injuries still occur So take this particular scenario you're out playing sport on one particular saturday and unfortunately you have a substantive injury to your knee or to your ankle you'd like to know whether you're at risk of subsequent development of osteoarthritis in that joint and what you could do at that time and or later to prevent the development of further symptoms and or structural changes in your joints We know that joint injury is a major factor
for the development of osteoarthritis and for any given injury for a knee for example about 50 of people will go on to develop osteoarthritis of that knee regardless of if they have a surgical intervention or not osteoarthritis which follows a significant joint injury is sometimes called post-traumatic osteoarthritis or Ptoa and many believe that ptoa represents a disease subgroup or phenotype of osteoarthritis joint injury is usually well defined and easy to pinpoint in time allowing opportunities to better understand the early mechanisms of osteoarthritis and pre-clinical research has provided further insights on the development of ptoa and
how certain molecules and pathways can be targeted to reduce Or prevent osteoarthritis following that joint injury and on this week's episode of joint action we're joined by dr fiona watt to discuss the prevention of osteoarthritis following injury fiona is a clinical reader in rheumatology in the department of immunology and inflammation at imperial college london having previously been an associate professor at the kennedy institute of Rheumatology at the university of oxford for a number of years at the university of oxford she completed her phd in cartilage biochemistry in 2009 she was appointed as an honorary consultant
rheumatologist in 2013. she leads the clinical translation theme within the center for osteoarthritis pathogenesis funded by versus arthritis In 2019 she was awarded a ukri future leaders fellowship a research interest aims to develop new predictive tests and treatments in high-risk groups for osteoarthritis hello fiona and welcome to the show hello david thanks for having me oh no it's an absolute pleasure and i'm really looking forward to this conversation and i think it's something that's Going to be really relevant to a large number of our listening audience but before we get into the main content i
just wanted a chance to get to know you a little bit better and hopefully for the listeners to do the same but can you tell me a little bit more about your background and what a typical day looks like sure i mean i i trained as a doctor and after medical school did my physician training decided i wanted to become a Rheumatologist actually because i was interested in really rare autoimmune diseases ironically rather than important conditions like osteoarthritis and it was actually during medical school i'd had my first research training and that sort of hooked
me in and i always knew i wanted to go back and i was training in west london and was aware of the kennedy institute of rheumatology and aware of what they were doing in osteoarthritis and really just Took the plunge to to go there and study further and i think was at the time quite an unusual area to be in and i also felt very strongly that i wanted a really good laboratory background so i actually did a laboratory science phd but then i've returned to doing more clinical and what we call translational work so
trying to bridge the lab and the clinic my normal working day i always say there isn't a normal day they vary quite a bit I think a lot of us are all spending quite a lot of time on online meetings but increasingly now they're in person as well with my team with collaborators managing projects i still do clinical work so see patients both in terms of our research in clinical trials and also in the nhs and i really love ultimately working with data and trying to find out new things so i try and park some
time for actually doing some of that and writing papers and so on as well which i Really like doing so that that's me wonderful and you know just probing a little bit further do you like the variety of your day in the fact that no day is the same and it sounds like you have a lot of different activities on your plate yeah i think that's one of the lures of research actually i mean if i compare myself to what i would have otherwise done which is being an nhs consultant Rheumatologist for all of my
week the structure is quite different and i quite like that i think i realized quite early on i was quite a goal-oriented person and i love i love the goal of the project the the thinking up the where we'd like to be and then trying to get there and i think research suits that type of mentality so yes i do i do quite like that that i i can't entirely predict how things will be one day to another you like that Distant challenge that you've got to try and attain yes i mean sometimes it can
feel too distant but um research tends to break things down into project size chunks so that can be doable and i do enjoy that i think that's good to sort of recognize that about yourself and how that might suit your work marvelous now if you know when you're not doing your day job what is it that you like to do yeah i think probably i work a little Too hard at the moment i think we all do but i'm a keen runner you'll often find me padding around the thames path in london which is near
to where i live which is very beautiful and i i love water so the thames is as near as i get in london and i really like travelling when i can so that's been difficult in the last couple of years but that's the scientific meetings and in my spare time and it was really great to get to berlin earlier this month and see other Researchers in osteoarthritis in person that was really exciting yeah it's it's definitely a wonderful refreshing change to see people in three dimensions as opposed to on a zoom screen as much as
zoom is a wonderful technology i'm fully over it and i'd much prefer to get back to face to face as regularly as we can now fiona if you had to describe yourself in five words what would they be ah this is difficult i think people Would say i'm enthusiastic i'm dedicated that can converge on being a bit driven as well i'm creative i'm also quite impatient and that includes my research and i think hopefully people recognize that it's right to be impatient in this area because we want to have some progress so i think that
suits that yeah all wonderful qualities and and i'm sure you obviously blend the optimism and Impatience together and hopefully drive things forward i try my best yeah because as we were saying a little bit before we got on to the recording you know i think some of the intransigence in the community and the lack of progress and they're not necessarily the same thing can be thwarted to some extent by people showing a little bit of impatience and being a little bit creative and taking Things from left field and pushing things forward so kudos to you
keep pushing thank you david um we'll try i think it's trying to take people with you is the important thing in this oh for sure yeah it's a village it's not it's not a solo activity so let's get into the content of today and i want to start by just i guess defining this area of post-traumatic osteoarthritis so what is it that we're actually talking about and How does that differ from garden variety osteoarthritis if at all yeah that's a good question so post-traumatic osteoarthritis is the term we use for osteoarthritis that follows a significant
joint injury and an example of that would be that someone may be familiar with would be an anterior cruciate ligament rupture like some footballers experience or tears of the meniscus in the knee and i'm giving Examples in the knee because that's probably the most studied joint but i think it's important to say that post-traumatic osteoarthritis can probably affect any of the joints that are affected by osteoarthritis in general i think that the question about how it differs from more usual osteoarthritis sometimes scientifically we call that idiopathic or primary osteoarthritis Is actually quite a hard one
we actually don't know the answer to that question and that's that's quite a thing to say but i mean let me say i think we all recognize that post-dramatic hostile authorities happens in younger people so from that point of view it looks a bit different there's a bit of discussion in the community about whether it's truly faster progressing more aggressive or not and i think that's that's actually difficult to say we lack evidence and of Course if you're watching for something you see it more often than you you do if you're not watching so that's
tricky it's used as a model of osteoarthritis so i think there's some assumption in the community that there is some crosstalk between the two processes but i think you know what i would say is that actually you know if you look at these the end points of these processes they look really really similar and i think we actually lack Evidence as to whether they're similar or different and that's one of the bits of of the work that we're doing is actually to understand that better yeah that's fantastic and just i guess to elaborate on that
a little bit further so obviously you know the other joints which we commonly see post trauma affecting include things particularly like the ankle but also sort of wrist and elbow and other spots as well but as you're you know alluding to i Guess the end stage pathology of the changes that occur in the joint are probably to a large extent somewhat indistinguishable but at least from an etiology so risk factor perspective probably the route to get there may be maybe subtly different so if a person you know in an ideal world we would prevent these
things from happening we prevent injuries from happening and that's been The subject of a couple of other podcasts that we've had with tim hewitt and jackie whittaker but obviously the focus of today is more around you know what can we do once someone's injured their joint or what what happens when they've injured the joint so when a person has that injury what makes them at increased risk of developing osteoarthritis following that injury Yeah again this is a really good question and very important both for sort of targeting treatment but also trying to explain to someone
what their personal risk might be and again i'd love to be able to tell you this more definitely there are some things we know but there are still some patchiness here so let me tell you what we do know so i think probably the strongest evidence for it is for around the type of the injury that you've had so some injuries Seem to have a higher risk than others okay so and i think you know if i give you some examples of that you know there are known risks i've mentioned anterior cruciate ligament rupture compared
to that you know what is at greater risk than that if you have additional injuries so an acl and a meniscal tear or other what we call concomitant injuries that will increase your risk fracture around the joint seems to be quite a potent risk factor dislocation So some of these bigger injuries and maybe that's common sense that the more extensive the damage the bigger your risk but that's what we see loud and clear in a number of studies i think there are some other questions around risk factors for oa as a whole so when we
look at established oa things like age sex how overweight you are are important risk factors actually they don't necessarily directly carry over here and we we need to know more here Actually what i can say is i think our work and others have clearly shown that how old you are at the time of the injury is associated with your risk so for every extra year that you are older you will incur some additional risk i think sex is an interesting one because actually there isn't the evidence i think for a female preponderance at least in
the same way as in osteoarthritis in terms of risk and that may be about the time in the Life course that this happens and i think more is needed to be known there and i think again there isn't conclusive evidence that how overweight or otherwise you are at the time of the injury affects your outcome it may do as things go on but you know you can hear from me that actually some of this risk factor profile might look a bit different so to your earlier question how different or similar it is you know maybe
there are some differences here i Think the other thing i would mention is the biology going on in the joint and we've spent a lot of time looking at this if we can look inside the joints and fluid in the joint are the things there that can help us predict risk and there we saw overwhelmingly that the amount of blood in the joint at the time of the injury i know that's not a nice thing to think about but when you pop an acl for example you will get blood in your joints the medical term
being a Hemorrhoisis and if there are large amounts of blood in the joint that associates with a worse outcome at least on symptoms i think it's harder to say around structure and the inflammation in the joint whether we measure that by looking at markers of inflammation or the amount of fluid you're collecting in the joint that also seems to adversely affect your outcome genes are important in a way and i just wanted to mention this because i think This is another uncertainty about the similarities or differences so we know a lot now about the genes
that are associated with osteoarthritis as a whole there are probably about 100 of them and most of them give you quite low individual risk but they're definitely there i think that much less is known about any genetic risk for developing osteoarthritis at the time of an injury and i say that because it's a slightly different question and again that's Something we want to be clear about because that could be a very important way of predicting risk if we could actually measure that either by talking to people about their family history or looking at genes wonderful
fiona what i might do is just ex get you to expand on a couple of the points you made primarily because you've done some really important work in this space and that's particularly around the blood in the joints and the Inflammatory biomarkers that you've looked at so you distinguished here between symptomatic and structural outcomes can you just explain that for a second and then let's dig back in a little bit to the blood and the joint and the inflammation and try to distinguish between those two and the effects that they have but i guess firstly
what do you mean by symptomatic outcomes when and what do You mean by structural outcomes yeah i think that's a really important question and this is something that carries over to osteoarthritis as a whole this is not just relevant for post-traumatic osteoarthritis so the symptoms are quite simply that they are symptoms of importance to someone with with an injury or with osteoarthritis and we'll often use questionnaires that measure these symptoms and we'll look across things Like pain and levels of pain functional um issues with the joint how active someone is what they're able to do
how much it's interfering with sport or everyday activities and you know clearly these things are important to people experiencing this they're important to clinicians who are trying to support people living with an injury or with osteoarthritis so we tend to put them front and center of how we think about trials and cohort studies and i i think That's right the problem we have is that they don't always associate directly with what's going on in the joint at a structural level when i say structure i mean literally that changes in the smooth surface of the joint
the cartilage changes in the bone around the sides of the joint changes in other soft tissue structures that we can measure on x-ray or on mri and they're also obviously from a clinical point of view also a hallmark Of osteoarthritis they're indisputable they can occur on their own without symptoms but you know obviously what we're thinking about here in terms of looking at the condition is both some symptoms but also some relevant structure but as i say what we've often found in injury is that at least early on there seems to be a dislink between
some of those things at least in some people so some people may have high symptoms but a lack of structural change Or vice versa now that may just be how we're looking and and how well we are able to pick up that structural change and i know this is something that you've spent a lot of time on in terms of osteoarthritis as a whole but i i hope that makes sense in terms of what we're trying to think about here for sure for sure and you know i guess just to dig into those particular points
a little bit further so the swelling That you saw from blood in the joint following an injury appeared to be related to symptoms but not necessarily to structure in the short term immediately following the injury up to what time period afterwards because i don't think you've had the chance at this point to follow these people out for decades for example yeah quite right i mean so the measurements that i was talking about earlier around blood and fluid was at The time of the injury so typically these people were recruited within about three weeks of their
injury to a maximum of eight weeks so that measurement would have been at that stage and then we are looking at symptoms or structural changes in this study that we've reported on two years after the injury so relatively short timelines we do have five-year data that's currently being analyzed but we can't you know we don't have that information and you're quite Right that that that measure of fluid in the joint being associated with symptoms was at the time of the injury in that sort of early window having said that and we did this in a
sort of discovery way that we looked at swelling at the three-month mark so quite soon after they were initially seen most of them had been operated on at that stage but persistent swelling at that three-month mark was one of the things that was associated with structural outcomes Interestingly so that was the only signal that we had there that that may be relevant i should say or for various reasons that there is not always complete data collection of x-rays and so on so sometimes we just lack the numbers to be clear on these things so it's
maybe that there wasn't an association but just that we didn't pick it up and that's always a challenge with cohort studies we always want bigger numbers than we have i guess Yeah and you know at least with the oftentimes described as blunt instruments that we're using to study people immediately following injury more often than not most people who have that injury tend to have a relatively good prognosis in at least in the short term so you know by 18 months to two years i think most of the people we're talking about here are relatively Free
of symptoms and structural changes is that a fair comment we have to have to wait for many years before we see them actually developing what we would classically call osteoarthritis symptoms or am i just correct me if i'm completely wrong i think it's difficult i think we again maybe we don't know enough in this area but i think in our experience in our cohort study that we're talking about at the moment actually if you look at People at two years there is a huge amount of variation and very few people are back to what we
would consider normal particularly a lot of these people were highly athletic individuals so obviously expecting to operate at a high level in terms of their knee and actually some people were really quite impaired still so i think this notion that people just quickly recover and get over it you know that there will be a few but there are plenty of people that Don't have the knee function and symptoms that they're they're hoping for i think to your second question about this sort of what seems to be a bit of a black box about well when
does this disease start i think again we should we saw some signal as i'm saying that early on people do seem to be getting structural change you know there are other studies out there that have detected this and the rates of this vary i think again how hard you look will Affect how frequent this is but even in our study if you considered the whole population we were seeing structural changes in at least 15 percent of people maybe higher because of what i said about not being able to look at these outcomes in everyone and
other studies have seen this so at five years looking by mri and another cohort study of people with acl ruptures about a third of them have got some structural changes in the knee that Would be consistent with osteoarthritis so not inconsiderable but the dynamics of how that happens when it happens i think we need to know far more about yeah and while we're talking about risk factors for subsequent development of osteoarthritis has been a lot of interest in as you mentioned the extent of the injury and how many other tissue structures and damage to to
bone and other structures occurs Um how quickly a person returns to play whether they have a re-injury whether they have surgery how important do you think those factors are in the in the prognosis story and their trajectory towards osteoarthritis development and is the data good enough to rest our hat on it or do we need more i think in the short answer is i think we need more i think one can make assumptions about some of these things but i think Actually and i know jackie whittaker you mentioned earlier has done a systematic review of
some of these factors and actually i think her conclusion her colleague's conclusion was that actually we need to know more about return to play it just clearly we don't have enough information to say this is the right time or this is too soon it's so complex because often these people are experiencing quite complex interventions uh different types of rehab program Different types of surgery going back to different things that this is quite difficult to get at actually and clearly is incredibly important to sport to individuals concerned i suspect there's a bit of a goldilocks you
know that it's not you don't want anything too soon or too long and that it may be quite particular to the individual and need to be quite personalized depending on whatever everything else is going on that's quite sounds quite woolly but i Think it's a very difficult area and i i think we certainly lack evidence to say you know this is right this is wrong at this point in time so more work to come and uh that might be a good segue basically to say you know we need to do more in this research base
and now the animal models that most people use to study osteoarthritis have very much relied upon this injury model what have we learned from those animal models thus far as as it relates to Uh treatment of injured joints yeah i mean i think it's first important to say well what are these models they are tend to be in small animals so mice rats typically where an injury is caused essentially either by a small operation so that's with the animals under anaesthetic it's important to say or some excessive loading or something that sort of tries to
copy an injury into a joint so causing an anterior Cruciate ligament rupture for example and because of the shorter lifespan rather than humans who develop as we're hearing osteoarthritis over years these animals tend to develop osteoarthritis-like changes over weeks depending on the model and so that then becomes quite helpful as a way of understanding some of the biology that's going on in the joints and also you know measuring change in the sort of shorter timeline experiments to understand the Disease can be done and i think it's fair to say there are various options out there
that they've all told us things and i think there's has to be quite careful thinking about what the question is i think in terms of which model might help you you know this is a difficult area but we think it's probably been an important one in terms of learning and knowledge because of course there's certain things we can't Get at in humans we can't look at tissues early on in the disease it wouldn't be ethical for me to go into someone who's just had a joint injury and say let me have a you know a
bit of your cartilage when we know that cartilage damage can increase the chance of oa we also have the benefit in mice particularly that they can be essentially the same animals they're genetically very very similar so Some of the variation that we see in humans that stopped us being able to get it you know underlying mechanisms goes away in that system so they're much cleaner in a way that you can ask very specific questions and for example even knock out genes so you can say well what is the role of a pathway or a particular
marker and actually take it out of that system either at birth or later on and actually understand how it's interfering with your system so i think you know What have we learned and we've learned quite a lot about what we've been talking about this mechanical disruption actually inducing inflammation in the tissues and that that may lead to damage and these animal models have given us a lot of information on that and perhaps what some of those critical pathways might be we've learned that it's a modifiable disease so this is not just the joint wearing out
but it's a cellular process and i say that because We can slow it down we can speed it up if it was just an inert process that wouldn't be the case in the same way but actually interfering with the biology can make a difference and that's a very important thing to take away because it tells us that we might be able to develop drugs that can intervene in this process successfully i think there are some things that are limitations here there always are and we need to be aware that a mouse is not a Human
that its tissues sometimes are different in terms of their thickness or maybe even some of the enzymes that break down the cartilage um but i think overall we and others have shown that actually you can learn from these platforms and then take them into humans and test more in humans and i i still feel that that is an important part of the field that this is how we may learn more about the disease in Humans superb now one of my close laboratory preclinical colleagues always brags about the fact that you know we've cured osteoarthritis thousands
of times in in mice models for example but failed to do that in our human condition what are the key limitations in translating those the knowledge about those models into that human condition you started touching upon them in your Last response but what are the the key limitations there and learnings that we need to take from those animal models and or adjust the human condition that we're studying because you know historically i think a lot of the osteoarthritis studies that we've done haven't necessarily focused on an injury model what do we need to do better
okay i mean i think i might be a little Controversial here and say that in oa we are often intervening at quite a late stage in the process so you know with a car the wheels are slightly uh worn out and the you know the motor isn't ticking over very well you know there's a real problem going on in the mouse models you've heard two things that we're actually changing things very early on either fundamentally in the mouse or at or near To a time of risk and i think that notion of early intervention may
be quite important here it's quite difficult and it may be important for osteoarthritis as a whole but actually the other point to make here is that these models are injury induced so is there a message here so you know are people being more successful because they're intervening in an injury-induced Situation now i'm not saying that that's necessarily a different disease but just again that they can hone in on on the window for the intervention and make a difference at the appropriate time and then they're actually seeing an outcome i think the other thing to say
is what i said before that they see this change because they have a much cleaner experimental system than we have in humans these you know if you've got mice or other animals that Are behaving in the same way you are more likely to see a signal for your intervention than in humans where we very marvelously vary hugely between each of us and have lots of different other things that we might consider about whether we might develop pain or might develop a structural problem so i think all of those things will feed into that success i
think the other thing i would say is we're really bad at carrying over What we've learned and i suspect we're going to talk a bit more about this but you know we might have you know a dozen maybe more molecular targets from these models that look promising but we've tested very few of those in humans so far so let's extrapolate onto that and really move the conversation in the direction of you know what have we proven to work in these pre-clinical models and i as you go through that Just differentiate a little bit between you
know treatment at the time of the injury or treatment subsequent to the development of structural change that could be equated to osteoarthritis because you know i think historically that's where we focused on in the human disease as opposed to focusing on treatment at the time of injury but what treatments are currently available for post-traumatic osteoarthritis from those pre-clinical Studies okay and i think it's important to say there's two things here one is is picking out targets and so that might be intervening in a pathway as i've said in a non-drug way and actually putting a
drug into an animal or a human and those two are sort of doing slightly different things i'm going to talk broadly here you know because i'm not going to get into some individual molecules necessarily but i i think that broadly speaking we are seeing that pathways Related to inflammation and this can be higher pathways that are controlling a whole host of other things that are going on if we block those can in some cases improve pain and an example of that would be a molecule called mcp1 or ccl2 i'll give one example um there are
other pathways that are lower down that are about the damage to the joint that are going on a classic example of that is a group of enzymes Called aggregases where we know from mouse models if we block those genetically at least that the disease gets better but remember there's a there's a flip side to this so there are also pathways that seem to be really important for repair and regeneration and we've seen that too and there obviously taking those out would actually make the disease worse so here the treatment would be putting in Something that
promotes repair and we've got some pathways there that are looking like they would promote repair the challenge here is is taking them into human and you asking me you know what works what works in human and actually very few of those treatments have been carried over into a human setting and there's a whole host of reasons for that but you know i think this is what we where we Would like to go i think there are two things here one we're talking about is how what effect they have but obviously we have to consider the
safety of these agents as well in the pre-clinical models the mouth models it's all about the efficacy we're kind of saying what works what has an impact on our pathway as we develop drugs we have to think about where else in the body is this affecting and you know is this actually something that would be safe in humans Given the differences between mouse and humans and that's where sometimes some of these targets are falling down because we're realizing that there are very important roles of these pathways in tissues other than the joint that mean that
they're not safe to target so there's a lot of work that can be done in pre-clinical models to actually predict this and learn quickly and sort of triage what we're looking at but yeah there's not nearly enough that's been Able to be carried over to human testing and some of that is actually not that there's not the potential for that but that we don't have a good framework for how we might test that in humans yet and just using your crystal ball for one second there fiona but if you were again to extrapolate from what
either you've seen in the pre-clinical models or at least some biologic data in the humans what would be the optimal treatment window for targeting inflammation Post injury and when would you like to target them with something that might be more reparative and up regulate some reparative process when would you go in and you may not have the answer but even if you just uh hypothesize yeah and i think it's a great question and and i think the answer may be broader than we think i mean the hypothesis here is there's this immediate response to the
injury and a Lot of what we've been looking at is that immediate response and how that maps onto a later response and so again from what we've been saying i would be talking about hours to days to maybe maximum of weeks where you would go in and actually target that response in real time with the hope of a improvement clearly there is a longer response in the joint around repair and resolution that Carries on for longer than that anyone who's experienced an injury will tell you it's many months of recovery time that we can probably
feed into so i suspect there is an interim window here where we can particularly do things like promote resolution or pick up people who are having persistent and unhelpful if i can call it that levels of inflammation remember we have to remember that inflammation is generally a good thing we have it in the Body to help us to repair and regenerate and we don't want to wipe it out and everyone all together at the start but this might be about picking out people who have abnormally high levels of certain aspects of it that are not
helpful and i think you know actually there may be an argument for doing this much later on you know at later points after injury but i think it will depend on the target and i think what we have to do for any particular pathway is Actually do the science and say where is this happening when is our window clearly the wider that can be will be more attractive probably for a pharmaceutical company but i would say if we if we give the analogy of a heart attack quite the same but it's similar and that there's
a sort of a sudden and urgent thing that happens we don't say okay you've had a heart attack let's see How you do over the next few months and we'll treat you if you get symptoms we now urgently intervene and i think at least for some targets around inflammation that may be the same here we may be saying you have had a joint attack and we can measure certain aspects of this that might pick out people who will do badly let's urgently intervene and so i think that would be my proposed model i think it's
really hard in terms of Us making sure that we're measuring the right things in terms of showing how well a treatment works because what we're talking about here is prevention and prevention is quite hard to measure yeah and just i guess taking that analogy a little bit further so in in heart disease when someone has presents with a heart attack we have markers that we can assess when they first present that give Us a sense of what their prognosis is likely to be and obviously you know whether that's the the cardiograph or or measurement of
a troponin or whatever it might be uh when they first present it gives us a sense of what the likely prognosis is and helps us i guess in terms of tailoring treatment to those who potentially have the worst prognosis or the worst the worst outcomes How far are we from doing that in osteoarthritis following injury i think we've got a way to go but i think the analogy is a really good one because i think again there we would be taking into consideration clinical factors things about the person things about that event and things that
we can measure that help us either to diagnose or predict outcome and i think the same is true here i think we are Further along you've heard from me that we do know and we can say certain things about risk factors and enhanced risk and how those fit together in a jigsaw is is obviously an important bit but actually it's probably you know going to be likely that if you've got six of those risk factors you're at higher risk than someone who's got one or none so i think we can already get some way there
i think the question You're asking me so is there a troponin you know marker is there a biomarker that can help and i think that's really critical because we can measure all kinds of things but if they don't substantially add to what we can already see in the patient then what why do them and i think that's the piece we have to do is say can we do better here can biology help us i think we're a long way along actually i think we're further than we think We've measured a lot of the right things
we're now getting up to scale where we're looking at thousands and hundreds of proteins and other markers rather than just a handful of things we think we might be interested in and i think that we are on the cusp of some big discoveries here and we should also from data sets that we have be able to say you know can we add to what we know can these things help us and i think if you can i mean your point Is a really important one you know some people will do well after this injury so
actually i think talking to people and we need to probably do this more you know that it is reasonable to propose that we should be picking out the people at the highest risk not just treating everyone because then you're exposing people to unnecessary safety there's a cost involved in treating everyone that if we can personalize and we do that in a Logic evidence basis of logical way that that is a sensible thing to do i think the other point here around you know this notion of giving a sort of a risk bracket i think is
a is about you know helping a person to understand and make those choices because i'm not saying that everyone will choose to go into a trial or take a a newer drug or have a particular intervention but it will give them a choice and it'll give them information That they don't currently have and i think that's a really important thing and i think although we might not have a perfect model the perfect system i suspect in the next two three years we should be able to come together and say what do we know what can
we say and improve on how we're thinking about this so let's expand on that point because you've spoken about the pre-clinical systems as very clean models What issues do you currently see with trial design and humans that you think there are good solutions to that we can that we can fix and or problems that we still need to solve in terms of that trial design for a post-traumatic osteoarthritis intervention okay so i'm going to talk specifically about post-traumatic oa although i think some of what i'm going to say will sort of carry over into oa
as a whole I mean i think the first thing to say is what we've already been talking about is if we include everyone in our studies and we're including people who are going to do fine anyway then it's going to be very difficult to show that a treatment works so actually picking out people at higher risk and thinking about that both in terms of the populations we include in our studies and whether we use markers and tests to actually help us to Refine that i think it's really important i think the other thing is at
the other end is what we're measuring at the other end and we touched on this earlier and you know this is going to be around symptoms because symptoms are important for people but it's also going to probably be around structure and and what you've heard is that early on we may not have a lot of signal going on for osteoarthritis the term that is Used by the pharmaceutical industry would be surrogate endpoints so things that we know that we can measure either a symptom or a structural change that associate well with a later change and
that's the bit that we really need to get at that's the bit that we don't have enough information on i think there are experts in the field like you and others who would have a good idea around the imaging measures that they thought might May be helpful both in terms of being associated with poor outcome or picking up the earliest changes of osteoarthritis so i think these are some of these things are unknown whether there are new things that you know that we don't know that we haven't fully tested that could be better i think
is something that we can look at but i think actually sitting down and gaining consensus from experts internationally in what our best thoughts are on this at This point is probably you know where where we need to be but i i think that they would be the two things that i would say are the probably the most important things in this area in terms of developing ptra i think the other thing i would say is you're hearing there's a lot of crossover as a whole so how we define early osteoarthritis in the general population is
actually really important here and i think probably i can't At the moment expect a reason why they should be different so actually being able to say this is our earliest point at which we can say someone has osteoarthritis could be really really important for helping these trials to happen because that could be then an end point in the trial and that's a wonderful response and a really thoughtful critical view of a really complex area and you've thought a lot about this next question that i want To ask and you've already started answering it with your
last response but what are the next steps that we need to take as a community in order to advance the field both in terms of knowledge but also interventions for people following injury you're right we've we all think about this a lot and we've been increasingly talking about it as well which i think is good and i i would say We need to do more of that so i think we've got some amazing groups working internationally in this area i think traditionally we've been in groups depending on whether we're interested in surgical interventions and we've
not talked about surgery much but clearly this is a commonly used treatment would be for example a surgical repair lots of trials going on in that area about best approaches here There are people who research exercise and other sort of supportive interventions and i should say exercise probably has you know the best evidence here and in oa as a whole and then there's people like me who are thinking more around drug targeting or some kind of pharmacological intervention and actually we're kind of at the moment thinking about these things separately and i would Very much
argue that we actually need to think about them collectively because actually if we're designing and running trials that look different to each other we'll never be able to learn from each other and actually to progress this field and actually even more importantly when we get something that we think works actually being able to generalize that to other settings to persuade Bodies that regulate treatments that we have something it's going to be terribly important that we have a sort of a shared framework for doing this and some shared outcomes and principles so i think this has
already started but i think we need a whole lot more of that to get us to a point where we can design really high quality trials where you know there's a huge amount of investment both from people taking part in these trials but also running them And the time involved so that we get there faster i said i was impatient at the start and i think you know what we all want is that we can get to the point where we have a treatment that works and we need the best thoughts on how we do
that yeah great thoughts and hopefully you get your wish of bringing the community together and breaking down those silos to reach consensus on those really important issues particularly as it relates Both to trial design but also hopefully some of the underlying biology that provides the prelude to all of that now i might joe quickly into the rapid fire question round so i'm just going to throw something at you and i just want you to come back to me with your immediate response so favorite book oh lord of the rings great books favorite movie Oh i
would say the english patience i'm a bit of a romantic i'm afraid dog or a cat person oh definitely dog marvelous that's a great response too favorite quote this is when i heard recently in a meeting i was at collaboration moves at the speed of trust it's really important given that what we've been talking about i think that's really important now what's your favorite food curry A tree brit it's very english yeah do you have a bad habit i'm afraid my husband would say it would be hoarding things i'm not a good one for being
tidy and throwing things away where would you next like to go on holiday oh i've thought about this a bit and i i think australia has to be top of my bucket list [Laughter] very thoughtful you're welcome down here anytime it is a lovely part of the world and what superpower would you have if you could have one i think the power of endless time i always want to do more than i have time for i'm sure we're all the same so i think that would help a great deal yeah and if you could meet
anyone dead or Alive who would it be i think mahatma gandhi is a very inspirational person and i would have been fascinated to be in his presence i agreed and what would you do if money were not an issue i think if i was the equivalent of bill gates i would set up an osteoarthritis foundation that was entirely focused on solving this disease just go and do that why don't you i mean It's about about time i'm gonna skip skip to my favorite question and ask you why you do what you do what's your motivation
i think ultimately it's to make a difference i think most of us in this area that's that's probably true but i get out of bed every day thinking you know i hope i can be a small piece in this jigsaw sorting out this this enormous problem that we have in terms Of this disease osteoarthritis yeah well all i can say is keep waking up feeling that way we need more people liking fiona so keep driving now is there any one piece of advice knowledge or wisdom that you'd like to give for people with osteoarthritis when
i'm sitting in clinics seeing someone with osteoarthritis i will generally say there is always something we can do you know it's really rare that people Walk into the clinic and that we've tried absolutely everything and actually you know because of the lack of information sometimes that's out there because of some of the lack of interest that maybe some of the clinical community show this disease generally there's something that can be done and i think particularly early on this notion that you know you are not on a conveyor belt towards joint replacement there's so much evidence
That this disease as you've heard is is reversible and we don't well we don't have all the treatments we'd like there are a lot of things um like exercise and like other therapies particularly when given in combination that can make a real difference so i think that's what i would pass on and that's a wonderfully positive and proactive message for all of our listeners to pay heed to and fiona i Just want to thank you for spending a little bit of time with us sharing such important insights and knowledge it's been a great privilege for
me and i'm hoping also for our listening community well thank you david for this opportunity i love talking about this area and i really hope that we can as a community come together to do more and uh i've really enjoyed talking about it with you so firstly thanks to fiona but also Thanks to you for your interest and enthusiasm for listening to this particular podcast a large proportion of people who develop osteoarthritis do so as a consequence of having prior injury to that joint oftentimes their symptoms occur many years after that initial injury and so
for example if an injury has occurred in a person's late teens or early 20s a lot of people are developing Symptomatic osteoarthritis in their 40s and 50s we've spoken today a little bit about what we know about risk factors that have a poor prognosis at the time of injury that may predispose both to shorter term symptoms but also to to some extent to structural change we've learnt a lot from animal models of osteoarthritis which In large part are injury-based models but at this point in time haven't necessarily translated a lot of that knowledge into the
human condition and so there's huge opportunities for us to better design and better understand treatment effects in human disease following injury and it's a great area of research a great area of active interest for many people within the field and i'm really looking forward to massive developments Over the next few years of which fiona will play a really pivotal role thanks again for your interest and enthusiasm for the podcast really look forward to talking to you again in the very near future and in the meantime please do take care of yourself [Music] thanks for listening
to joint action with david hunter if you like our show and want to know more visit Www.jointaction.info if you have any questions you can email us at hello at jointaction.info and follow us on twitter at jointactionorg this podcast is hosted by david hunter edited by vicky dwong music produced by jordan hunter the information posted on this podcast is not intended to diagnose treat cure or prevent disease anyone seeking medical advice should consult a health professional [Music]
